Document Type : Research Articles
Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand.
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok, Thailand.
Excellent Center for Drug Discovery (ECDD), Mahidol University, Bangkok, Thailand.
Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
Center of Excellence on Environmental Health and Toxicology (EHT), Faculty of Science, Mahidol University, Bangkok, Thailand.
Objective: Gambogic acid (GA) has been reported to induce apoptosis in cholangiocarcinoma (CCA) cell lines. However, the molecular mechanisms underlying its anti-cancer activity remain poorly understood. This study was aimed to investigate GA’s effect on human CCA cell lines, KKU-M213 and HuCCA-1, and its associated mechanisms on Wnt/β-catenin signaling pathway. Methods: Cell viability, apoptosis, and cell cycle analysis were conducted by MTT and flow cytometry. The effect of GA mediated Wnt/β-catenin and ER stress were determined by luciferase-reporter assay, qRT-PCR, and western blot analysis. Results: GA exhibited potent cytotoxicity in CCA cells which was associated with significantly inhibited cell proliferation, promoted G1 arrest, and activated caspase 3 mediated-apoptosis. GA attenuated β-catenin transcriptional levels, decreased β-catenin protein, and suppressed the expression of c-Myc, a downstream target gene of Wnt/β-catenin signaling. GA activated genes involved in ER stress mechanism in KKU-M213 and enhanced CCA’s sensitivity to gemcitabine. Conclusion: Our findings reveal that the molecular mechanism underpinning anti-cancer effect of GA is partially mediated through the inhibition of Wnt/β-catenin signaling pathway and induction of ER stress induced-apoptosis. GA may serve as a promising therapeutic modality for amelioration of gemcitabine-induced toxicity in CCA